Journal
MOLECULAR ONCOLOGY
Volume 10, Issue 10, Pages 1559-1574Publisher
WILEY
DOI: 10.1016/j.molonc.2016.09.005
Keywords
Ovarian cancer; DBeQ; ML240; Salubrinal; ER stress; Unfolded protein response; CB-5083; Synergy
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Funding
- University of Kansas Endowment Association
- University of Kansas Cancer Center Support Grant [P30-CA168524]
- Cancer Center Cancer Biology program
- American Cancer Society Research Scholar [125618-RSG-14-067-01-TBE]
- Department of Defense Ovarian Cancer Research Program [W81XWH-10-1-0386]
- NIH/NIGMS COBRE grant [P30 GM103326]
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Valosin-containing protein (VCP) or p97, a member of AAA-ATPase protein family, has been associated with various cellular functions including endoplasmic reticulum-associated degradation (ERAD), Golgi membrane reassembly, autophagy, DNA repair, and cell division. Recent studies identified VCP and ubiquitin proteasome system (UPS) as synthetic lethal targets in ovarian cancer. Here, we describe the preclinical activity of VCP inhibitors in ovarian cancer. Results from our studies suggest that quinazoline-based VCP inhibitors initiate G1 cell cycle arrest, attenuate cap-dependent translation and induce programmed cell death via the intrinsic and the extrinsic modes of apoptosis. Mechanistic studies point to the unresolved unfolded protein response (UPR) as a mechanism by which VCP inhibitors contribute to cytotoxicity. These results support an emerging concept that UPR and endoplasmic reticulum (ER) stress pathways may be targeted in ovarian cancer as a source of vulnerability. Since prolonged ER stress may result in CHOP-mediated cell death, we tested the hypothesis that VCP inhibitors act synergistically with compounds that enhance CHOP expression. Here, we show that VCP inhibitors act synergistically with Salubrinal, an inhibitor of eIF2 alpha dephosphorylation, by enhancing CHOP expression in ovarian cancer cell lines. Our results provide a proof-of-concept that VCP inhibitors can be used as a single agent and can be synergized with compounds that enhance CHOP expression to induce cell death in ovarian cancer cells. (C) 2016 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
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